This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Loss of DNA mismatch repair causes one of the most common hereditary cancer syndromes. Msh2 is a significant player in DNA mismatch repair. Mutations in the MSH2 gene account for 30% of the cases of this hereditary cancer syndrome. We studied a class of clinically identified MSH2 missense mutations (resulting in a single amino acid change in the 934 amino acid protein) using yeast as a model system. Our research showed that inadequate levels of the variant Msh2 proteins was the most common reason for failure of DNA mismatch repair among the panel of oncogenic missense variants. We will collaborate with the Yeast Resource Center to develop technologies to facilitate assaying the functional consequences of mutations in MSH2 and other DNA repair genes linked with cancer. These new methods will allow us to study alleles with multiple point mutations and combinations of alleles, all with a higher throughput than we are presently capable of performing.